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A 21-year-old woman was admitted with altered consciousness and hyperammonemia. She was diagnosed as having adult-onset type II citrullinemia (CTLN2) by DNA analysis. The patient had mutations of the SLC25A13 gene, which were compound heterozygotes of 851 del 4 and IVS11+1G>A. CTLN2 has a poor prognosis, in spite of various intensive medications, and we performed a living related partial liver transplantation (LRLT). Over a 2-year follow-up, the patient has been well. CTLN2 can be diagnosed by the DNA analysis and can be treated by LRLT.

Complexation of zinc(II) and cadmium(II) ions with 2,2′-bipyridine (bpy) are studied in N,N-dimethylacetamide (DMA) by calorimetry. Formation constants, enthalpies, and entropies of five mononuclear complexes, [Zn(bpy)n]2+ (n=1–3) and [Cd(bpy)n]2+ (n=1,2), are determined, and compared with the corresponding values in an analogous but less bulky solvent, N,N-dimethylformamide (DMF). The zinc complexes are more stable and the formation is more exothermic in DMA than in DMF, whereas the solvent effect on the cadmium complexes are rather small. A largely positive value of the enthalpy of transfer of Zn2+ from DMF to DMA shows that the greater stability of the zinc complexes in DMA is due to the weaker solvation of the metal ion, which is caused by the steric hindrance of DMA molecules. The transfer enthalpies become smaller in the order Zn2+>[Zn(bpy)]2+>[Zn(bpy)2]2+>[Zn(bpy)3]2+ and dictate gradual relaxation of the steric effect in the complexes. On the other hand, the transfer enthalpies of Cd2+ and its complexes are all small, indicating that the hindrance is insignificant in the vicinity of this larger cation.

We investigated the effect of tryptophan (Trp) on exocrine secretory function, using isolated rat pancreatic acini. Trp inhibited cholecystokinin-octapeptide (CCK-8)-stimulated amylase secretion, causing a downward shift in the dose-response curve. The inhibitory effect of Trp was dose-dependent and was observed only on the sustained secretion, there being no effect on the initial phase of amylase secretion. Trp (10 mM) also inhibited amylase secretion in response to carbachol and bombesin, as well as fluoride, a potent activator of guanine-nucleotide binding proteins. Since Ca2+ influx is necessary for sustained secretion, we examined the effect of Trp on Ca2+ influx and efflux. Trp increased the CCK-8-stimulated Ca2+ influx rate without affecting Ca2+ efflux, suggesting that Trp elevates intracellular Ca2+ levels. Increasing intracellular Ca2+ levels with A23187 resulted in the inhibition of CCK-8-stimulated amylase secretion. These results indicate that Trp inhibits CCK-stimulated sustained amylase secretion, in part by increasing Ca2+ influx into acinar cells.

The complexation of manganese (II), cobalt (II) and zinc(II) with thiocyanate ions has been studied in N,N-dimethylacetamide (DMA) by calorimetry and spectrophotometry at 298 K. In these metal systems the formation of a series of four isothiocyanato complexes, [M(NCS)n](2-n)+ (n = 1÷4; M = Mn, Co, and Zn) was established, and their formation constants, enthalpies and entropies were determined. Interestingly, the complexation behavior in DMA is significantly different from that in N,N-dimethylformamide (DMF), despite of the similarity of the physicochemical properties of these solvents. The complexation is indeed enhanced significantly in DMA over DMF and is more exothermic in the former solvent. Furthermore, with cobalt(II) an octahedral to tetrahedral coordination geometry change was found to occur in DMA at an earlier step of complexation than in DMF. These results suggest that six-coordination of DMA molecules to a metal ion is severely sterically hindered.

The complexation of manganese(II), cobalt(II) and nikel(II) with bromide ions has been studied in N,N-dimethylacetamide(DMA) by calorimetry and spectrophotometry. The formation of [MBr]+, [MBr2] and [MBr3]− (M=Mn, Co, Ni) was revealed in all the metal systems. Interestingly, the complexation is significantly enhanced in DMA over N,N-dimethylformamide (DMF). This is unusual because physicochemical properties of DMA and DMF as solvent are similar. Furthermore, extracted electronic spectra of individual complexes of NiII suggested the presence of a geometry equilibrium, [NiBr(DMA)5]+=[NiBr(DMA)4]++ DMA, in DMA. A similar geometry equilibrium is also suggested, [NiBr2(DMA)3]=[NiBr2(DMA)2]+DMA. Such geometry equilibria were not observed in DMF. With regard to cobalt(II), electronic spectra show the presence of the four-coordinated [CoBr(DMA)3]+ complex in DMA, unlike the six-coordinated [CoBr(DMF)5]+ one in DMF. These facts suggest that a specific strong steric interaction operates between coordinating solvent molecules, which plays a key role in the complexation behavior of the divalent transition metal ions in DMA.

Solution equilibria between zinc(II) and halide ions have been studied in N,N-dimethylacetamide (DMA) by calorimetry at 298 K. Formation constants, enthalpies, and entropies of mononuclear binary complexes, [ZnIICln](2−n)+ (n = 1—4), [ZnIIBrn](2−n)+ (n = 1—3), and [ZnIIIn](2−n)+ (n = 1,2), have been determined. In addition, mixed-ligand complexes have been detected in ternary Zn–Cl–Br and Zn–Br–I systems: [ZnClBr], [ZnCl2Br]−, [ZnClBr2]−, and [ZnBrI]. Complexation is more favorable and more exothermic in the order Cl > Br > I. Formation of the monohalogeno complexes is particularly endothermic and entropy-productive, suggesting that geometric transition from octahedral to tetrahedral is complete at this step, i.e., all the halogeno complexes are tetrahedral. Thus, the transition occurs earlier in DMA than in N,N-dimethylformamide (DMF). Compared with DMF, complexation in DMA is more favorable and more exothermic exclusively at the first and second steps, and little difference is found for the later steps....

血管周皮腫 (hemangiopericytoma) はまれな腫瘍であり, 1942年にStoutらにより, はじめて他の血管系腫瘍から独立した腫瘍として報告された. 胃原発の血管周皮腫の1例を経験したが, 胃原発の本腫瘍はきわめてまれな疾患であり, 本邦では自験例を含め16例の報告をみるに過ぎない.症例は74歳の男性. 腹部腫瘤を主訴に近医受診. 当科へ紹介入院となる. 胃透視では胃体部大彎側の圧排像を認めたが粘膜面の変化は認められなかった.腹部超音波, CT検査では, 左上腹部に嚢胞を伴った腫瘤像を認めた. 血管造影では右胃動脈を栄養血管とする腫瘍像が認められた. 開腹所見では, 胃壁外性に発育した腫瘤が大網に被覆されていた.腫瘤の他臓器への癒着, 浸潤はみられず, 明らかなリンパ節の腫脹は認められなかった. 病理組織学的には, 血管周皮腫であった.術後14か月を経過してるが再発, 転移の徴候は認められていない.

Background/Aims: Insulin is shown to exert various regulatory effects on the exocrine pancreatic function. We investigated the direct effect of insulin on exocrine pancreatic secretion. Methods: The effects of insulin on amylase release, 125I-secretin binding and Na+- and K+-activated adenosine triphosphate phosphohydrolase (Na+,K+-ATPase) activity were measured using the isolated rat pancreatic acini. Results: Insulin potentiated the amylase release elicited by secretin plus cholecystokinin (CCK), but not by either secretin or CCK alone. The potentiating effect of insulin was dependent on the concentration and preincubation time. Insulin had no effect on 125I-secretin binding. Ouabain, a specific Na+,K+-ATPase inhibitor, caused a concentration-dependent inhibition of the potentiated secretion by insulin without affecting the secretory response to secretin plus CCK. In membranes prepared from acini treated with insulin, Na+,K+-ATPase activity was significantly increased. Similar results were obtained when acini were treated with insulin in combination with secretin plus CCK. Conclusions: Insulin exerts a direct effect on pancreatic acinar cells and potentiates exocrine secretion elicited by secretin in combination with CCK, in part, by increasing Na+,K+-ATPase activity.

Dear Editor, HIVor HHV-8-related primary effusion lymphoma (PEL) is a rare and poor prognostic disease which presents as serous effusion without detectable tumor masses. PEL occasionally has both immunoglobulin (Ig) and T cell receptor (TCR) gene rearrangements, so-called genotypic infidelity [1, 2]. Recently, HIV-negative HHV-8-unrelated primary effusion lymphomalike lymphoma (PEL-LL) has been reported, and some cases are associated with c-MYC amplification. Although HHV-8 virus antigen can increase c-MYC stability in PEL [3], c-MYC expression in PEL-LL has not been confirmed so far. A 76-year-old male had suffered from esophageal cancer, which responded to chemoradiotherapy. Three years after treatment, however, he had experienced cough, general fatigue, and night sweats. Physical examination revealed no breath sounds on the right hemithorax. Chest X-ray showed severe pleural effusion in the right lung (Fig. 1a). However, no tumor mass or lymphadenopathy was detected. Gastrointestinal fiberscope showed no sign of esophageal cancer recurrence. Complete blood count and serum biochemistry studies were as follows: WBC 7,170/μl, hemoglobin 10.6 g/dL, platelet 402,000/μl, AST 20 IU/L, ALT 12 IU/L, LDH 377 IU/L, total bilirubin 0.4 mg/dL, and sIL-2R 525 U/ml. Serological tests for HIV, HTLV-1, and HCV were negative. Bone marrow was intact. In analysis of pleural effusion, there were many large atypical lymphocytes which were positive for CD19, CD20, CD30, CD79a, and Ig lambda light chain but negative for CD10 and CD56 (Fig. 1b). HHV-8 and EBVencoded RNA by immunochemistry were negative. There was a small fraction of normal T cells. Eighty percent of lymphocytes were Ki-67 positive. Southern blot analysis of tumor cells demonstrated Ig heavy chain (IgH) as well as TCR rearrangement (Fig. 1c). Karyotype analysis showed complex karyotype, including add(8)(q24) and c-MYC amplification, and these cells strongly expressed c-MYC protein by immunostaining (Fig.1d). He was diagnosed with PEL-LL and was treated with six courses of R-CHOP. He remains alive and well with slight pleural effusion without additional therapy for more than 18 months. There are only two cases of PEL-LL with both IgH and TCR rearrangements. The first case is a pleural cavity-based T cell-rich B cell lymphoma [4]. Actually, it was reported for this lymphoma to show the dual gene rearrangement [5]. It could be bi-clonal lymphoma, of which the T cell clone was derived from abundant background Tcells. The second case is post-liver transplant effusion lymphoma [6]. It demonstrated incomplete TCR-β rearrangements by PCR; wherein, these rearrangements can be found in some B cell lymphomas [7]. In our case, most cells in the effusion were B cells. In addition, we confirmed both rearrangements by southern blot analysis (Fig. 1c). Therefore, we believe that this is the first definitive case of genotypic infidelity in PEL-LL. In addition, we confirmed strong c-MYC expression on tumor cells along with T. Kashiwagi :K. Minagawa :H. Kawano : T. Hirata : S. Kashiwagi :Y. Nakagawa : S. Kusaka : T. Suzuki : T. Inagaki : M.Kishi :N.Miwa : S. Kimura :M. Takechi :M. Koide :M. Iwai : T. Matsui Department of Internal Medicine, Nishiwaki Municipal Hospital, Nishiwaki, Hyogo 677-0043, Japan

We investigated the regulatory effect of cholecystokinin (CCK) on subsequent insulin binding to pancreatic acinar cells. Rat isolated acini were preincubated with various concentrations of CCK octapeptide (CCK-8) at 37 degrees C. Acini were then washed, resuspended in the binding buffer, and incubated with 8.3 pM 125I-labeled insulin for 60 min at 37 degrees C. Pretreatment with CCK-8 caused inhibition of subsequent 125I-insulin binding that was time and concentration dependent. Significant inhibition was observed with 3 pM CCK-8. Computer analysis of the competition-inhibition study with a nonlinear least-squares curve-fitting program revealed that CCK-8 pretreatment of acini reduced the receptor affinity of the high-affinity binding site. This inhibitory action of CCK-8 was not due to the alteration in degradation or internalization of the tracer. When acini were pretreated with 100 pM CCK-8 for 120 min at 4 degrees C, a reduction in the receptor affinity of the high-affinity binding site was also observed. In pancreatic membrane prepared from acini preincubated with 100 pM CCK-8 for 120 min at 37 degrees C, displacement of 125I-insulin (83 pM) by unlabeled insulin (24 degrees C, 1 h) revealed that CCK-8 inhibited 125I-insulin binding by altering the receptor affinity of the high-affinity binding site. In acinar preparations the inhibitory effect of CCK-8 on 125I-insulin binding was abolished when acini were preincubated with CCK-8 and CCK receptor antagonist L 374718 at 37 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

We often have difficulties in dignosing an abdominal tumor as a non-functioning islet cell tumor preoperatively, because it has no characteristic symptoms. Subsequently, very few cases of the tumor have been reported thus far. A 47-year-old female was admitted to our hospital because of upper abdominal discomfort. Physical examinations revealed a fist-sized and elastic hard tumor in the upper abdomen. Ultrasonography and Computed tomography showed two tumors in the abdomen. One of them was found in the right lobe of liver and the another in the body and the tail of pancreas. Selective angiography revealed hypervascular tumors. No elevated serum levels of various endocrine hormones were noted. Accordingly, those tumors were diagnosed as non-functioning cel tumors preoperatively and the patient underwent resection of the pancreas and right lobectomy of liver. Postoperative histopathological and immunohistological examinations revealed malignancies. A case of malignant non-functioning islet cell tumor with liver metastasis was reported, together with a review of the literature.

The solvation structure of divalent transition-metal ions, manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and zinc(II), in N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMA) has been studied by the EXAFS (extended X-ray adsorption fine structure) method. All the metal ions examined show the coordination number n=6, suggesting a six-coordinate octahedral structure in DMF. The manganese(II), cobalt(II), nickel(II), and copper(II) ions also show n=6 in DMA as well as in DMF

The aim of this study was to clarify the effect of ethanol on stimulus-secretion coupling in pancreatic exocrine secretion. We investigated the effects of 600 mM ethanol on cholecystokinin octapeptide (CCK-8)-stimulated amylase release, cytosolic free Ca 2+ concentration ([Ca 2+ ] i ) and Ca 2+ fluxes using in vitro isolated rat pancreatic acini. Ethanol, given alone, stimulated both the initial and the sustained phases of amylase release. On the other hand, ethanol inhibited only the sustained phase of amylase release stimulated by CCK-8. Ethanol also inhibited amylase release in response to fluoride, a direct activator of guanine nucleotide-binding protein, suggesting that ethanol affects intracellular signal transduction molecules. Ethanol had no influences on the initial rise but increased the sustained rise in [Ca 2+ ] i stimulated by CCK-8 and inhibited CCK-8-stimulated Ca 2+ outflux without affecting Ca 2+ influx. 8-Bromoguanosine 3' :5'-cyclic monophosphate, a membrane-permeable analogue of cGMP regulating membrane Ca 2+ -pump activity in various cells, completely reversed the ethanol-induced inhibition of amylase release and Ca 2+ outflux in response to CCK-8 as well as fluoride. Given that Ca 2+ plays a critical role in stimulus-secretion coupling in pancreatic exocrine secretion, our results indicate that 600 mM ethanol inhibits CCK-8-stimulated amylase release by inhibiting Ca 2+ -pump activity on the plasma membrane.

The role of intraduodenal bile in regulation of plasma cholecystokinin (CCK) levels were investigated in patients with obstructive jaundice under external bile diversion and under physiological bile flow into the duodenum by internal bile drainage. Basal plasma CCK levels determined by a specific and sensitive bioassay in patients under external bile drainage (2.2 +/- 0.2 pmol/liter; mean +/- SE) were significantly higher than those in control subjects (1.0 +/- 0.3 pmol/liter). In control subjects, the peak CCK response (6.2 +/- 0.7 pmol/liter) to a test meal was seen at 45 min, whereas that in patients under external bile drainage, it was seen at 20 min after a test meal (17.6 +/- 3.2 pmol/liter; P0.01 vs controls). After peak response, plasma CCK levels in controls gradually decreased, but remained significantly elevated during a 3-hr observation period. In patients under bile diversion, the test meal caused a prompt plasma CCK peak, with a transient fall followed by a continuous rise until 180 min postprandially. In six patients, external bile diversion was changed to internal biliary drainage with a stent tube within two weeks to maintain physiological bile flow into the duodenum. Internal bile drainage normalized basal (0.9 +/- 0.2 pmol/liter) as well as meal-stimulated CCK release (peak value: 5.0 +/- 0.8 pmol/liter). These results demonstrate that endogenous bile exerts tonic inhibition on basal and postprandial plasma CCK levels in humans.

To clarify the effect of islet hormones on pancreatic ductular cell function, we measured the exocrine secretion elicited by 10 pM secretin in the presence or absence of islet hormones using an isolated perfused rat pancreas model. Insulin significantly increased secretin-stimulated pancreatic juice secretion, but not protein secretion. The potentiating effect of insulin on pancreatic juice secretion was concentration-dependent, and the maximal effect was observed with 1 microM insulin. Ouabain, a specific Na+,K(+)-ATPase inhibitor, caused concentration-dependent inhibition of the potentiating effect of insulin without affecting secretin action. Glucagon (100 nM) significantly inhibited secretin-stimulated pancreatic juice secretion and also tended to inhibit protein secretion. A somatostatin analog, SMS 201-995 (10 nM) significantly inhibited both the pancreatic juice and protein secretion stimulated by secretin. The inhibitory effect of SMS 201-995 was concentration-dependent and was maximal at 1-10 nM. These results demonstrate that insulin potentiates the secretory response to secretin, at least partly by increasing Na+,K(+)-ATPase activity, whereas glucagon and somatostatin inhibit this response. Thus, pancreatic islet hormones regulate the secretory function of pancreatic ductular and centroacinar cells.

Background: Exocrine pancreatic function is influenced by pancreatic islet hormones. Although the existence of somatostatin receptors has been shown on pancreatic acinar cells, the in vitro effect of somatostatin on exocrine secretory function has not been established. Methods: Using isolated rat pancreatic acini, the effect of somatostatin analog SMS 201-995 (SMS) and somatostatin 14 (S-14) on amylase release, cyclic adenosine monophosphate (cAMP) production, and hormone binding were determined. Results: SMS inhibited the potentiating effect of secretin on amylase response to cholecystokinin octapeptide (CCK-8) in a concentration-dependent manner. The inhibitory effects of SMS and S-14 were similar on a molar basis and were observed when vasoactive intestinal polypeptide (VIP) but not 8bromoadenosine 3′:5′ cyclic monophosphate was used instead of secretin and when carbachol, bombesin, A23187, and 12-O-tetradecanoylphorbol 13-acetate were used instead of CCK-8. SMS inhibited secretin-induced cAMP production, and the dose-inhibition curve for cAMP was similar to that for amylase release. SMS had no influence on 125 I-secretin and 125 I-VIP binding. Conclusions: Somatostatin acts directly on acinar cells and inhibits secretin potentiation of secretory response in part by inhibiting secretin-induced cAMP production.

Involvement of endogenous cholecystokinin (CCK) in the development of acute pancreatitis induced in rats by closed duodenal loop (CDL) was examined, and the effects of the potent and specific CCK receptor antagonist loxiglumide on this model of acute pancreatitis were evaluated. Plasma CCK bioactivity was markedly elevated 3 and 6 h after onset of acute pancreatitis. A single subcutaneous injection of 50 mg/kg body wt of loxiglumide 30 min before the induction of acute pancreatitis completely eliminated the hypercholecystokinemia. Loxiglumide given 3 h after the induction of acute pancreatitis suppressed plasma CCK bioactivity, which had risen up to 30-fold over basal value (0 h) at 3 h, to nearly the basal level. Loxiglumide pretreatment, in addition, significantly prevented the rise in serum amylase and lipase activity, as well as the increase in ascitic volume. It also ameliorated histological alterations of hemorrhagic and necrotizing pancreatitis. Reduction of plasma CCK bioactivity by loxiglumide after the onset of pancreatitis slowed the rate of progression of pancreatitis. However, pancreatic wet weight and cellular infiltration were not significantly influenced by loxiglumide treatment. These observations suggest that endogenous CCK is not involved in the initiation of acute hemorrhagic and necrotizing pancreatitis induced by CDL, but is involved in the development of pancreatitis in this model.

We examined the effect of fasting on the course of experimental acute pancreatitis induced in rats by four subcutaneous injections of 20 micrograms/kg body weight of cerulein at hourly intervals. Rats were either fasted from 24 hr before to 9 hr after the first cerulein injection or fed ad libitum throughout the experiment. Twenty-four hours of fasting reduced cerulein-induced increases in serum levels of amylase and anionic trypsin(ogen) to 50 and 70% of those in fed rats, respectively. Increases in pancreatic wet weight after cerulein injections were also less in fasted rats than in fed rats. Pancreatic content of trypsin was significantly decreased after a 24-hr fast, and no further changes were induced by cerulein injections. The histological signs of acute pancreatitis were greatly alleviated by fasting. However, 24 hr of fasting did not alter the sensitivity and responsiveness of the exocrine pancreas to cerulein in both in vivo and in vitro. Plasma CCK bioactivity and immunoreactive secretin concentration in 24-hr-fasted rats were significantly lower than those in fed rats. Administration of CCK receptor antagonist, loxiglumide, 12 hr prior to the induction of acute pancreatitis reduced the increase in serum amylase activity in fed rats to nearly the same levels as that in fasted rats and alleviated histological signs of pancreatitis to some extent. These present observations suggest that fasting lessens the severity of cerulein-induced acute pancreatitis by reducing endogenous CCK release.

The effects of proglumide-related cholecystokinin (CCK) receptor antagonists CR 1409 and CR 1392 on CCK-octapeptide (CCK-8)-stimulated immunoreactive insulin (IRI) release and exocrine secretion were examined simultaneously in the isolated perfused rat pancreas. The CR 1409, at concentrations of 10-100 nM, significantly inhibited CCK-8 (100 pM) stimulation on IRI release but failed to inhibit the stimulatory effect of CCK-8 on both pancreatic juice flow and protein secretion. Increasing concentrations of CR 1409 inhibited both CCK-8-stimulated IRI release and exocrine secretion. Half-maximal inhibition was observed with approximately 2 nM for IRI release and 1 microM for protein secretion. When a higher dose (1 nM) of CCK-8 was used, the inhibitory effect of 10 nM CR 1409 on CCK-8-stimulated IRI release was abolished, whereas 10 microM CR 1409 retained significant inhibitory effect. Furthermore, 1 microM carbachol-induced IRI release was not altered by the addition of 10 microM CR 1409. The CR 1392 also had an inhibitory effect on both CCK-8-stimulated IRI release and exocrine secretion. The concentration of CR 1392 that caused half-maximal inhibition of CCK-8-stimulated IRI release was 300 times lower than that of exocrine secretion. In addition, 1 microM carbachol-stimulated IRI release was not altered by 100 microM CR 1392. Thus, the inhibitory effects of CR 1409 and CR 1392 on IRI release were mediated through the interaction at the CCK receptor and were more potent than those on juice and protein secretion. This study suggests, therefore, that CCK receptors on B cells might be different from those on acinar cells in terms of their relative affinities for antagonists.

Effect of Gymnema sylvestre , R.Br. ( G. sylvestre ; GS 4 ) on glucose homeostasis was studied in rats. In the first set of experiments, the acute effect of GS 4 was examined in both non-diabetic and streptozocin (30 mg/kg)-induced mildly diabetic rats. Administration of 1 g/kg body weight of GS 4 to 18-h fasted non-diabetic rats significantly attenuated the serum glucose response to oral administration of 1 g/kg glucose. The immunoreactive insulin (IRI) response in GS 4 -administered rats was lower, but not significantly, than that in control rats. In mildly diabetic rats, a 60 min increment in serum glucose concentrations was significantly reduced by GS 4 administration. No IRI response was observed in these diabetic rats irrespective of GS 4 administration. In the second set of experiments, the chronic effect of GS 4 was examined in mildly diabetic rats. Two weeks after the induction of diabetes, the rats were divided into two groups that had similar impairment of glucose tolerance assessed by an oral glucose loading test. The rats were fed for 32–35 days with either a control diet or a diet supplemented with GS 4 . After 4 weeks, GS 4 showed a tendency to reduce the serum glucose concentrations in the fed state and to improve the glucose tolerance. Gain in body weight, food intake, pancreas weight and the pancreatic contents of IRI, protein, amylase and trypsinogen were unaltered in the GS 4 -treated group compared with the control. These results suggest the usefulness of G. sylvestre in the treatment of certain classes of non-insulin-dependent diabetes mellitus.

We examined the inhibitory effect of L-364,718, a nonpeptide cholecystokinin (CCK) antagonist, on CCK stimulation of pancreatic exocrine and endocrine secretion in both the isolated pancreatic acini and the isolated perfused pancreata of rats. In the isolated acini, L-364,718 inhibited CCK octapeptide (CCK-8)-stimulated amylase release and binding of 125I-CCK-8 in a dose-dependent manner without appreciable effects on the basal amylase secretion. L-364,718 also inhibited amylase release in response to caerulein and gastrin I, but had no effect on amylase release stimulated by other secretagogues or by agents bypassing receptors. Similarly, binding of N-methylscopolamine to pancreatic acini was not inhibited by L-364,718. In the isolated perfused pancreata, L-364,718 inhibited CCK-8-stimulated pancreatic exocrine secretion and insulin release. The inhibitory effects of L-364,718 were more potent for insulin release than for exocrine secretion and persisted even after the removal of L-364,718 infusion. These results clearly demonstrate that L-364,718 is a specific, potent, and prolonged antagonist of CCK's stimulatory actions on pancreatic acinar and B cells.

We examined the biological and histologic characteristics of a new experimental model of acute necrotizing pancreatitis induced by excessive doses of arginine in rats. Rats were given a single intraperitoneal injection of 500 mg/100 g body weight of L-arginine. At 12-24 hr after the arginine injection, serum levels of amylase, lipase, and anionic trypsin(ogen) reached respective peak values 2, 5, and 20 times those of control rats without arginine and returned to control levels after 24-48 hr. The contents of pancreatic protein, DNA, and digestive enzymes were markedly reduced after the arginine injection and reached their nadirs at 72 hr. After 14 days these levels were almost normal. Histologic examination revealed a number of small vesicles within acinar cells at 6 hr, which were identified as markedly swollen mitochondria by the electron microscope. Other intracellular organelles and nuclei also showed degenerative changes. At 12 hr interstitial edema appeared, and acinar cell necrosis was seen after 24 hr. The extent and severity of necrotic changes of pancreatic exocrine tissue with inflammatory cell infiltration were maximal at 72 hr. At seven days, pancreatic acinar cells began to regenerate, and pancreatic architecture appeared almost normal after 14 days. The present study has demonstrated that the administration of excessive doses of arginine induces a new, noninvasive experimental model of acute necrotizing pancreatitis.

Solution equilibria of beryllium(II) and cadmium(II) complexes with halide and thiocyanate ions are studied in N,N-dimethylacetamide (DMA) by calorimetry. Mononuclear BeII complexes, [BeX]+ and [BeX2](X = Cl, SCN), and CdII complexes, [CdX]+, [CdX2], [CdX3]– and [CdX4]2–(X = Cl, Br, I, SCN), are found, and their formation constants, enthalpies and entropies are determined. The BeII systems are also studied in N,N-dimethylformamide (DMF). Each of the BeII complexes has very similar thermodynamic quantities in DMA and in DMF, in sharp contrast to first-row transition metal(II) complexes where a marked solvent effect has been observed. In spite of the very small size of the cation, steric hindrance of DMA is absent in the four-coordinate solvation structure of Be2+. ΔH°n and ΔS°n for the CdII complexes in DMA are largely different from those in DMF, which shows the steric solvent effect of DMA, i.e. steric hindrance does exist in the six-coordinate structure of this fairly large cation. When combined, these results offer clear evidence for the octahedral-specific nature of the steric hindrance in metal–DMA interactions.

The complexation of nickel(II) with thiocyanate (SCN–) ions has been studied by titration spectrophotometry and calorimetry in N,N-dimethylacetamide (DMA) containing 0.2 mol dm–3(n-C4H9)4NBF4 as a constant ionic medium at 298 K. All the experimental data were well explained in terms of the formation of four mononuclear [Ni(NCS)n](2–n)+(n= 1–4) complexes and their formation constants, enthalpies and entropies were determined, together with their intrinsic electronic spectra. The intrinsic spectra were also extracted at 278 and 318 K, and their temperature dependence clearly demonstrated the presence of solvation equilibria, i.e. an equilibrium between two structural isomers with different numbers of bound solvent molecules. This is not the case for the NiII–SCN– system in N,N-dimethylformamide, where all the mono-, di-, tri- and tetra-thiocyanato complexes have a single structure of an octahedral six-coordination. These facts imply that the coordination of solvent molecules in the first solvation shell of the metal ion is strongly sterically hindered with DMA.

The formation of chloro complexes of manganese(II) and cobalt(II) has been studied in N,N-dimethylacetamide (DMA) by calorimetry and spectrophotometry. Formation constants, enthalpies and entropies of four mononuclear complexes [MIICln](2–n)+(n= 1–4) have been determined for M = Mn and Co at 298 K and for M = Mn at 318 K. In spite of the similar solvent properties of DMA and N,N-dimethylformamide (DMF), overall formation of [MCl4]2– is strongly favoured and less endothermic in DMA than in DMF. Electronic spectra of the CoII complexes obtained at 278, 298 and 318 K indicate an octahedral geometry for [Co(DMA)6]2+ and tetrahedral geometries for [CoCl(DMA)3]+, [CoCl2(DMA)2], [CoCl3(DMA)]– and [CoCl4]2– at each temperature, though an additional solvation equilibrium is observed for the monochloro complex: [CoCl(DMA)5]+⇌[CoCl(DMA)3]++ 2DMA. The relatively large values of ΔH°1 and ΔS°1 suggest that extensive desolvation occurs on formation of the monochloro complex. Thus, the coordination geometry primarily alters at an earlier step (n= 1) in DMA than in DMA (n= 2). For the MnII system, large ΔH°n and ΔS°n values (n= 1, 2) are also diagnostic of an earlier transition from octahedral to tetrahedral geometry in DMA. The results show that the stability and structure of the complexes are strongly controlled by sterically hindered solvation of DMA molecules towards the metal ion, leading to the more favourable, less endothermic complexation and the tendency to form a less-crowded solvation structure. The steric effect of DMA is more pronounced in the order MnII < CoII < NiII.

症例は56歳男性で発熱を主訴として来院した. 7年前に胆嚢穿孔にて手術を受けている. 来院時体温37.4度, 白血球増多, CRP陽性, 血沈の昂進などの炎症所見があり, 腹部CT, 超音波検査, 血管造影で肝左葉に径6cm大の腫瘤を認めた. 穿刺吸引細胞診所見では, 大型な長円形, 紡錘形の細胞が散在性に認められ, 核は増大し, なかには好酸性に染まる大きな核小体があり, class Vと判定した. 穿刺肝生検組織所見では繊維細胞の増生と小円形細胞浸潤像, 多核巨細胞が認められ肉芽腫と診断し腫瘤切除術を行った. 摘出腫瘤は9×7×4.5cm大で繊維性の被膜に覆われ, 弾性軟で割面は黄白色であった. 組織学的には膠原繊維, 繊維芽細胞の増生とリンパ球主体の高度な細胞浸潤像, また多数の多核の巨細胞, そして散在性に石灰化巣などが認められ, 炎症性肉芽腫と診断した. 自験例の細胞診像をretrospectiveにみると, 細胞, 核, 核小体の増大が著しく良性との断定は困難であるが, クロマチンの増量, 凝集は軽度であり再生性の変化と判断すべきであった. 今後, 肝腫瘤の細胞診像の検討にあたり, まれではあるが炎症性偽腫瘍も念頭におくべきと考えられた.

胃癌症例34例に経静脈的糖負荷試験を施行し, その成績をstage別, 癌腫の大きさ別に比較検討した. stage別ではstage I, II, III, IVの4群に, また癌腫の大きさ別では早期癌をA群, 進行癌を腫瘍長径が5cm以内をB群, 5～10cmをC群, 10cm以上をD群の4群に分けた. 血糖値はstage III, IVおよびC群がそれぞれstage I, A群にくらべ有意に高値を示した. IRIはC群, D群がA群にくらべ有意に低値を示した. Insulinogenic IndexはC, D群が, ΣIRIはD群がA群にくらべ有意に低値を示した. 以上, stage III以上, 腫瘍径5cm以上の進行癌で耐糖能低下が認められた. この耐糖能低下の原因として癌患者の栄養低下による影響が大きいと考えられた.

Isolated rat pancreatic acini were most sensitive and responsive when stimulated directly with cholecystokinin octapeptide (CCK-8) without preincubation. Both the responsiveness and sensitivity of acini to CCK-8 decreased time dependently with prolonged preincubation. When acini were stimulated with CCK-8 following pulse labeling with radioactive leucine, old protein was discharged together with newly synthesized (labeled) protein. However, the sensitivity and responsiveness of these acini for release of labeled protein were primarily reduced with preincubation, indicating that newly synthesized protein was contributing to the time-dependent loss of sensitivity and responsiveness. Then isolated acini were treated with 300 microM cycloheximide for 2 h. This treatment prevented the decreases in the sensitivity and responsiveness of amylase release to CCK-8 stimulation and made these alterations in one series of experiments negligible. Using these acini, a sensitive and specific bioassay for the measurement of CCK in human and rat plasma was developed.

D,L-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxypropyl-pentylami no)-5- oxopentanoic acid (CR 1505; loxiglumide) is a newly developed analog of proglumide. We examined the inhibitory effects of loxiglumide on pancreatic exocrine function in the isolated pancreatic acini and the isolated perfused pancreata of rats. Loxiglumide inhibited cholecystokinin octapeptide (CCK-8)-stimulated amylase release and, similarly, binding of [125I]CCK-8 to isolated rat pancreatic acini. Loxiglumide was about 3000 times more potent than the reference substance proglumide, but was about 1000 times less potent than L-364,718, another new CCK antagonist having benzodiazepine ring, in inhibiting CCK-8-stimulated amylase release. The inhibitory effect of loxiglumide displayed competitive kinetics and was specific for CCK in that the effects of other receptor secretagogues or agents bypassing receptors were not altered. The inhibitory effect of loxiglumide was fully reversible in isolated acini. However, the pancreata perfused with 10 microM loxiglumide for 20 min did not respond to CCK-8 for more than 20 min even after the removal of loxiglumide infusion. In contrast, an immediate increase in pancreatic exocrine secretion was observed after proglumide removal. Loxiglumide appeared to be bound to the receptors on acinar cells in a slowly dissociating state. These results indicate that loxiglumide acts as a potent, competitive, and specific CCK antagonist on the exocrine pancreas and, because of its prolonged inhibitory action, may be useful as a therapeutic agent in pancreatic disease.

The effects of proglumide analogue. CR 1392, on pancreatic exocrine secretion were studied in the isolated pancreatic acini and the isolated perfused pancreata of rats. In the isolated acini, CR 1392 caused a parallel rightward shift of the dose-response curve for amylase secretion stimulated by cholecystokinin octapeptide (CCK-8). CR 1392 inhibited maximally stimulated amylase release by CCK-8 (100 pM) in a concentration-dependent manner, with a half maximal inhibition (ID50) at 8.0 +/- 0.6 microM. CR 1409, another proglumide analogue, also caused a concentration-dependent inhibition (ID50: 3.2 +/- 0.4 microM). Although CR 1409 was about 2.5-fold more potent than CR 1392 in inhibiting the stimulated amylase release, 1 mM CR 1409 caused 107.4 +/- 0.9% increase in amylase release, suggesting acinar cell damage. CR 1392 (1 mM) also caused 19.9 +/- 2.3% increase in amylase release, but was less toxic than CR 1409. The antagonism produced by CR 1392 was selective for CCK and had no effect on amylase release stimulated by other receptor secretagogues or by agents bypassing receptors. CR 1392 added 20 min after the CCK-8 stimulation rapidly abolished pancreatic exocrine secretion in both isolated acini and isolated perfused pancreas. Although the inhibitory effect of CR 1392 was fully reversible in the isolated acini, the pancreata perfused with 100 microM CR 1392 for 20 min did not respond to the subsequent stimulation with CCK-8 for more than 20 min. These results indicate that CR 1392 is a potent, competitive, specific and long acting antagonist of CCK in rat pancreas.